IMI - oral biopharmaceutics tools project - evaluation of bottom-up PBPK prediction success part 1: Characterisation of the OrBiTo database of compounds.

Predicting oral bioavailability (Foral) is of importance for estimating systemic exposure of orally administered drugs. Physiologically-based pharmacokinetic (PBPK) modelling and simulation have been applied extensively in biopharmaceutics recently. The Oral Biopharmaceutical Tools (OrBiTo) project (Innovative Medicines Initiative) aims to develop and improve upon biopharmaceutical tools, including PBPK absorption models. A large-scale evaluation of PBPK models may be considered the first step. Here we characterise the OrBiTo active pharmaceutical ingredient (API) database for use in a large-scale simulation study. The OrBiTo database comprised 83 APIs and 1475 study arms. The database displayed a median logP of 3.60 (2.40-4.58), human blood-to-plasma ratio of 0.62 (0.57-0.71), and fraction unbound in plasma of 0.05 (0.01-0.17). The database mainly consisted of basic compounds (48.19%) and Biopharmaceutics Classification System class II compounds (55.81%). Median human intravenous clearance was 16.9L/h (interquartile range: 11.6-43.6L/h; n=23), volume of distribution was 80.8L (54.5-239L; n=23). The majority of oral formulations were immediate release (IR: 87.6%). Human Foral displayed a median of 0.415 (0.203-0.724; n=22) for IR formulations. The OrBiTo database was found to be largely representative of previously published datasets. 43 of the APIs were found to satisfy the minimum inclusion criteria for the simulation exercise, and many of these have significant gaps of other key parameters, which could potentially impact the interpretability of the simulation outcome. However, the OrBiTo simulation exercise represents a unique opportunity to perform a large-scale evaluation of the PBPK approach to predicting oral biopharmaceutics.

Bilinear decomposition based alignment of chromatographic profiles.

A novel alignment procedure for chromatographic signals with photodiode array detection is presented. At first, the complexity of the chromatographic signals is reduced by chemometric resolution of the pure constituents. For this, the application of multivariate curve resolution-alternating least squares leads to the decomposition of the multiway data block into a chemically meaningful bilinear model representing the chromatographic profiles and their spectral signatures. The flexible implementation of a spectral selectivity constraint allows the background to be differentiated from the constituent spectra. Hereby, the pure concentration profiles are obtained which are consequently individually aligned by correlation optimized warping. In its final step, the procedure reconstitutes the original data with the aligned chromatographic profiles and their corresponding spectra. The alignment is evaluated for two sets of chromatographic signals. The new procedure improves the original application of correlation optimized warping minimizing the risks of aligning noncorresponding chromatographic information.

Quality control of Citri reticulatae pericarpium: exploratory analysis and discrimination.

Extracts of Citri reticulatae pericarpium (PCR) are commonly used in the Traditional Chinese Medicine. The quality control of PCR is currently performed by single marker analysis, which can hardly describe the complexity of such natural samples. In this study, a fingerprint methodology for PCR based on high-performance liquid chromatography (HPLC) was developed and validated. A total of 69 fingerprints of authenticated PCR samples, commercial PCR samples, mixed peel samples, and other Citrus peels were recorded. Exploratory data analysis allowed optimizing the extraction procedure and detecting mixed peel samples. Once the optimizations were performed and the method validated, discrimination between the authentic PCR samples and all other samples was performed by p-Discriminant Partial Least Squares. The established model was able to differentiate between classes with a high reliability for each sample. Furthermore, evaluation of the score and loading plots of the model indicated nobiletin, tangeretin, naringin and hesperidin as important markers for the quality control of PCR.

Identification by LC-ESI-MS of flavonoids responsible for the antioxidant properties of Mallotus species from Vietnam.

Several Mallotus species (Euphorbiaceae) are used in Vietnam as edible plants or as traditional medicines for different indications, some related to the treatment of inflammatory diseases. This study investigated the antioxidant activities of 33 samples from 17 Vietnamese Mallotus species. We also evaluated potential cytotoxic activity against human cervix carcinoma HeLa and human lung fibroblast WI-38 cells. Our aim is to develop safe dietary supplements with a protective effect against various diseases caused by tissue damage and the acceleration of the aging process linked to reactive oxygen species. These tests allowed the identification of non-cytotoxic plant species exhibiting significant antiradical properties. These antioxidant properties may be explained by their polyphenol composition. The antioxidant activity of the most active Mallotus species was further analyzed with and without tannins removal. We also identified by LC-ESI-MS some flavonoids responsible for a part of this activity.

Chromatographic separation techniques and data handling methods for herbal fingerprints: a review.

As herbal medicines have an important position in health care systems worldwide, their current assessment and quality control are a major bottleneck. Over the past decade, major steps were taken not only to improve the quality of the herbal products but also to develop analytical methods ensuring their quality. Nowadays, chromatographic fingerprinting is the generally accepted technique for the assessment and quality control of herbal products. This paper briefly considers the evolution of the regulations and guidelines on the quality control of herbal medicines, and reviews the established analytical techniques for herbal fingerprinting with an emphasis on the most recent developments, such as miniaturized techniques, new stationary phases, analysis at high temperatures and multi-dimensional chromatography. Accessory to the new analytical techniques, the chemometric data handling techniques applied are discussed. Chemometrics provide scientists with useful tools in understanding the huge amounts of data generated by the analytical advances and prove to be valuable for quality control, classification and modelling of, and discrimination between herbal fingerprints.